PROJECT SUMMARY The goal of this project is to develop an efficacious, safe and well-tolerated pharmacotherapy to treat thyroid eye disease (TED); a highly distressing, painful and sight-threatening orphan condition for which there is no approved therapy. Current approaches for managing TED are unsatisfactory due to limited efficacy, side effects and safety issues. The mainstay of treatment is a series of surgical procedures directed to repairing the orbit once the active phase of the disease has run its course. TED is associated with Graves's disease and has an autoimmune mechanism wherein autoantibodies interact with orbital tissues to cause inflammation, tissue proliferation and edema. The resulting increase in tissue volume within the bony confines of the orbit forces the eyeballs forward out of their sockets resulting in pain, optic nerve compression, loss of vision, restricted ability to move the eyes, diplopia, corneal ulceration, and a disturbingly altered appearance. With respect to molecular mechanism, a growing body of evidence, from ex vivo assays using orbital tissue from TED patients, suggests that insulin-like growth factor 1 receptor (IGF-1R) plays important roles in regulating the autoimmune response that underlies TED. Most importantly from a therapeutic perspective, ex vivo assays show that inhibiting IGF-1R function completely prevents the autoimmune activation of orbital fibroblasts, which are the primary cellular target of the autoimmunity. RV 001 (teprotumumab) is a high potency, high specificity monoclonal antibody antagonist of human IGF-1R. RV 001 was initially taken into clinical development as a possible cancer therapy and is being re-purposed to treat TED. Preclinical toxicology studies and experience in > 750 oncology patients show that RV 001 is safe and well-tolerated at pharmacologically active exposures. The specific aims of the project are to execute a randomized, double-masked, placebo-controlled Phase 2 clinical study to determine whether inhibition of IGF-1R with RV 001 is efficacious in reducing the major symptoms of TED and is safe and well- tolerated in TED patients. RV 001 will be given early in the progression of the disease - within 6 months of the diagnosis of eye symptoms - and at a dose that previous pharmacokinetic measurements and pharmacodynamic biomarker studiess in humans indicate produces > 90 % occupancy of IGF-1R. The study is statistically powered to give an unequivocal readout of efficacy. The study has the potential to be one of two pivotal clinical trials needed for registration of RV 001 as the first approved therapy to prevent the suffering and disfigurement experienced by TED patients.